ARTICLE OPEN ACCESS Mitochondrial diseases in North America An analysis of the NAMDC Registry Emanuele Barca, MD, PhD, Yuelin Long, MS, Victoria Cooley, MS, Robert Schoenaker, MD, BS, Correspondence Valentina Emmanuele, MD, PhD, Salvatore DiMauro, MD, Bruce H. Cohen, MD, Amel Karaa, MD, Dr. Hirano [email protected] Georgirene D. Vladutiu, PhD, Richard Haas, MBBChir, Johan L.K. Van Hove, MD, PhD, Fernando Scaglia, MD, Sumit Parikh, MD, Jirair K. Bedoyan, MD, PhD, Susanne D. DeBrosse, MD, Ralitza H. Gavrilova, MD, Russell P. Saneto, DO, PhD, Gregory M. Enns, MBChB, Peter W. Stacpoole, MD, PhD, Jaya Ganesh, MD, Austin Larson, MD, Zarazuela Zolkipli-Cunningham, MD, Marni J. Falk, MD, Amy C. Goldstein, MD, Mark Tarnopolsky, MD, PhD, Andrea Gropman, MD, Kathryn Camp, MS, RD, Danuta Krotoski, PhD, Kristin Engelstad, MS, Xiomara Q. Rosales, MD, Joshua Kriger, MS, Johnston Grier, MS, Richard Buchsbaum, John L.P. Thompson, PhD, and Michio Hirano, MD Neurol Genet 2020;6:e402. doi:10.1212/NXG.0000000000000402 Abstract Objective To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry. Methods This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists. Results One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with POLG1 and PDHA1 being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants. Conclusions The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America. From the Department of Neurology (E.B., V.E., S.D., K.E., X.Q.R., M.H.), Columbia University Medical Center, New York; Department of Biostatistics (Y.L., V.C., J.K., J. Grier, R.B., J.L.P.T.), Mailman School of Public Health, Columbia University, New York; Radboudumc (R.S.), Nijmegen, The Netherlands; Department of Pediatrics (B.H.C.), Northeast Ohio Medical University and Akron Children’s Hospital; Genetics Unit (A.K.), Massachusetts General Hospital, Boston; Department of Pediatrics (G.D.V.), State University of New York at Buffalo; Departments of Neurosciences and Pediatrics (R.H.), University of California at San Diego; Department of Pediatrics (J.L.K.V.H., A.L.), University of Colorado School of Medicine, Aurora; Department of Molecular and Human Genetics (F.S.), Baylor College of Medicine, Houston, TX; Texas Children’s Hospital (F.S.), Houston; Joint BCM-CUHK Center of Medical Genetics (F.S.), Prince of Wales Hospital, ShaTin, New Territories, Hong Kong; Department of Neurology (S.P.), Cleveland Clinic, OH; Departments of Genetics and Genome Sciences and Pediatrics (J.K.B., S.D.D.), and Center for Human Genetics, University Hospitals Cleveland Medical Center, Case Western Reserve University, OH; Departments of Neurology and Clinical Genomics (R.H.G.), Mayo Clinic, Rochester, MN; Department of Neurology (R.P.S.), University of Washington, Seattle Children’s Hospital; Department of Pediatrics (G.M.E.), Stanford University, Palo Alto, CA; Department of Medicine (P.W.S.), University of Florida at Gainesville; Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai (J. Ganesh), New York; Mitochondrial Medicine Frontier Program (Z.Z.-C., M.J.F., A.C.G.), Division of Human Genetics, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine; University of Pennsylvania Perelman School of Medicine (Z.Z.-C.), Philadelphia; Department of Neurology (M.T.), McMasters University, Toronto, Ontario, Canada; Department of Neurology (A.G.), Children’s National Health Network, Washington, DC; Office of Dietary Supplements (K.C.), National Institutes of Health, Bethesda, MD; and Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.K.), National Institutes of Health, Bethesda, MD. Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by NIH U54 NS078059. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary CoQ COX cPEO IRB 10 = coenzyme Q10; = cytochrome c oxidase; = chronic progressive external ophthalmoplegia; = institutional review board; LS = Leigh syndrome; LHON = Leber hereditary optic neuropathy; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF = myoclonus epilepsy with ragged red fibers; MtD = mitochondrial disease; mtDNA = mitochondrial DNA; NAMDC = North American Mitochondrial Disease Consortium; nDNA = nuclear DNA; OxPhos = oxidative phosphorylation; PDC = pyruvate dehydrogenase complex; SLE = stroke-like episode; TP = thymidine phosphorylase. Mitochondria are the organelles that generate cellular energy history, physical examination, and laboratory tests and pro- (adenosine triphosphate) via oxidative phosphorylation vide written consent using IRB-approved forms. Clinicians (OxPhos). OxPhos is an elaborate multiprotein machine input data using a secure web-based data entry system. Data composed of a series of enzyme complexes embedded in the were collected through December 1, 2018. inner mitochondrial membrane (complex I–V).1 Because virtually all tissues require mitochondria to function, mito- Data availability chondrial dysfunction manifests commonly as multisystem The NAMDC Clinical Registry data are stored in a secure disorders, with frequent involvement of high-energy demand database and are available to other investigators on sub- tissues, such as brain, muscle, and heart.2 The OxPhos system mission of a data use application and approval by the consists of 85 subunits and is under the control of 2 genomes, NAMDC Data Use Committee. the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial diseases (MtDs) can arise due to Clinical diagnosis pathogenic variants in either of the 2 genomes.3 Because of Participants are enrolled in the Registry based on the ’ the genetic complexity and the multiple biochemical functions NAMDC site investigators clinical diagnoses of MtDs. Di- of these organelles, MtDs are phenotypically and genetically agnoses are based on established and published clinical 6,7 fi ff heterogeneous. Because of this vast diversity, these disorders criteria. Twenty- ve di erent clinical diagnoses were are challenging to diagnose, manage clinically, and investigate coded: 15 classical mitochondrial clinical syndromes and 8 fi with an association of symptoms and signs commonly ob- scienti cally. Epidemiologically, MtDs are considered rare 8–12 diseases, but among rare disorders, they are relatively fre- served in mitochondrial participants (table 1). Some of quent, with an overall estimated prevalence of 11.5:100,000.3 the syndromes require an association of clinical and radiologic fi In totality, MtDs represent the most prevalent group of ndings, e.g., for the diagnosis of leukoencephalopathy, white inherited neurologic disorders.4 Disease registries constitute matter lesions evident on brain MRI are typically associated a cornerstone of MtDs patient care because they help to es- with cognitive impairment, long-tract signs, or both. En- fi tablish a reliable picture of the distribution and characteristics cephalopathy was de ned by the presence of dementia, seiz- of the participants, focus resources, and gather accurate data ures, corticospinal tract dysfunction, movement disorders, or for efficient clinical mechanistic studies and therapeutic trials.5 combinations of these manifestations due to cerebral This article reviews the spectrum of clinical, biochemical, and pathology. molecular genetic features of MtD participants enrolled in the fi North American Mitochondrial Disease Consortium Two nonspeci c groups of participants with complex clinical (NAMDC) Registry (hereafter referred to as the Registry). manifestations that do not fall in any of the other categories are (1) multisystemic and (2) other clinical disorders. For multisystemic disease, clinical manifestations